Cancer cells overexpress IF₁, the endogenous protein that inhibits the hydrolytic activity of ATP synthase when mitochondrial membrane potential (Δμ_H⁺) falls, as in ischemia. Other roles have been ascribed to IF₁, but the associated molecular mechanisms are still under debate. We investigated the ability of IF₁ to promote survival and proliferation in osteosarcoma and colon carcinoma cells exposed to conditions mimicking ischemia and reperfusion, as occurs in vivo, particularly in solid tumors. IF₁-silenced and parental cells were exposed to the FCCP uncoupler to collapse Δμ_H⁺ and the bioenergetics of cell models were validated. All the uncoupled cells preserved mitochondrial mass, but the implemented mechanisms differed in IF₁-expressing and IF₁-silenced cells. Indeed, the membrane potential collapse and the energy charge preservation allowed an increase in both mitophagy and mitochondrial biogenesis in IF₁-expressing cells only. Interestingly, the presence of IF₁ also conferred a proliferative advantage to cells highly dependent on oxidative phosphorylation when the uncoupler was washed out, mimicking cell re-oxygenation. Overall, our results indicate that IF₁, by allowing energy preservation and promoting mitochondrial renewal, can favor proliferation of anoxic cells and tumor growth. Therefore, hindering the action of IF₁ may be promising for the therapy of tumors that rely on oxidative phosphorylation for energy production.

Cervical cancer has a high incidence and mortality, and is one of the leading causes of cancer-related deaths among women worldwide. The infection with high-risk subtypes of the human papillomavirus (HPV) represents a crucial factor in the development of precancerous lesions. HPV oncoproteins target multiple host factors to promote uncontrolled cellular proliferation, genomic instability, profound metabolic reprogramming, resistance to apoptosis and immune evasion. Thus, cervical carcinogenesis involves metabolic reprogramming in patient cells, such as enhanced aerobic glycolysis, and altered glutamine, lipid and mitochondrial metabolism, which collectively support the bioenergetic and biosynthetic demands of cancer cells. Cancer cells also activate several mechanisms to adapt and survive under hypoxic/anoxic conditions. The mechanisms underlying cervical carcinogenesis often involve non-coding RNAs. This review aims at summarizing the mechanisms and factors involved in the development and progression of cervical cancer following HPV infection, and offers an overview of the available therapies that have been developed for this disease.